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Anatomy of a : A (H1N1) 2009

Abstract The H1N1 2009 has reached pandemic status and is currently infecting hundreds of thousands of people, spreading efficiently since being isolated in Mexico in April 2009. In this review, the current pandemic state of H1N1 will be discussed along with the symptoms and severity of illness caused by the virus and how they compare to previous . A number of diagnostic tests are available for the rapid detection of the H1N1 2009 and are discussed, along with management of infection and the emergence of antiviral resistance. A has currently been licensed for use against the H1N1 2009 virus and its effectiveness will be addressed, along with prevention measures that should be taken to hinder further spread of the virus. Keywords: Influenza A virus, H1N1 subtype, disease outbreaks, influenza, human, virus replication, virus shedding, influenza , , .

Royal College of Surgeons in Student Medical Journal 2010; 3: 51-55.

Introduction The current influenza outbreak has been classified Influenza A viruses have long caused human as phase 6 by the WHO, indicating that the virus pandemics. The current pandemic virus is a direct has reached full pandemic status and has the descendent of the influenza A H1N1 outbreak of capability to cause sustained outbreaks in 1918 (the ‘’), which killed an populations across the globe. All WHO pandemic estimated 50 million people worldwide.1 In April phases are illustrated in Figure 1.5 2009, a novel triple- swine-origin H1N1 2009 had been steadily influenza A virus was isolated from a patient in increasing worldwide until reaching a peak in late Mexico, and quickly spread worldwide. This is the October 2009. Decreases in infection indices first influenza A virus pandemic since the H3N2 were observed in many countries throughout influenza outbreak of 1968, which November, with the amount of hospitalised cases killed an estimated one to two million people.1 As of H1N1 2009 decreasing by 50% in Ireland.4,1 of November 15, 2009, 206 countries have Although the drop in influenza cases may appear reported 6,770 deaths due to H1N1 2009 to the to indicate that the worst of the pandemic has World Health Organisation (WHO).2 In contrast, passed, this may in fact be due to the natural seasonal influenza A result in three to progression of the pandemic. Influenza Adam C Brady five million severe infections worldwide, with pandemics typically progress in waves, and a RCSI medical student 250,000-500,000 deaths annually.3 Ireland has decrease in the amount of cases may indicate the reported 3,914 confirmed cases, with 16 deaths end of a wave of infections, with potentially more due to H1N1 2009 as of November 14, 2009.4 outbreaks to come.6

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PHASE 5-6/ PANDEMIC POST PHASES 1-3 PHASE 4 POST PEAK PANDEMIC

Time

Predominantly Sustained human to Widespread Possibility of Disease activity at animal infections; human transmission human infection recurrent events seasonal levels few human infections

FIGURE 1: Pandemic influenza phases. Source: WHO.

Influenza A virus Pathogenicity of the virus Influenza viruses are classified by their core proteins as influenza A, B, or It is of great benefit to use previous pandemics as models to assess C.1 Influenza A is a negative sense RNA orthomyxovirus containing eight the potential of the H1N1 2009 virus for widespread infection and genetic segments, which code for 10 different proteins7 (Table 1).1,8-10 loss of life. Pathogenicity of viruses is often determined by the

Influenza A is further classified by the surface antigens haemagglutinin reproduction number (R0), which indicates the average number of (H) and neuraminidase (N). Sixteen H and nine N alleles exist, coding for infections caused by a single person with the illness. The 144 possible unique surface antigen combinations.11 In addition, reproduction number for H1N1 2009 is estimated to be between mutations in the influenza genome can result in antigenic drift, 1.4 and 1.6.14 This is more transmissible than the seasonal influenza introducing new viral subtypes into the population and altering the virus, which has a mean R0 of 1.3, and less transmissible than the 15 pathogenicity of individual virus strains. 1918 pandemic, which at its peak had an estimated mean R0 of 2.0. When two viral subtypes co-infect the same host, genetic shift can occur. Genetic shift results from the swapping of one or both genomic Table 2: Influenza pandemics. segments encoding H and N between two different influenza subtypes. Year/name Strain Estimated deaths Pigs are frequently infected with human and strains, and thus are thought to be prime organisms for facilitating the creation of 1918 ‘Spanish flu’ H1N1 20-50 million new strains of influenza via genetic drift. In the case of H1N1 2009, the 1957-‘58 ‘Asian flu’ H2N2 2-4 million virus was originally endemic in swine and adapted to cause widespread infection in humans.12 Pandemics arise when a virus undergoes genetic 1968-‘69 ‘’ H3N2 1-2 million shift resulting in a novel H surface protein. Rapid spread through large populations occurs due to an absence of previous immunity to the new 1977 ‘Russian flu’ H1N1 0.7 million H antigen, which contributed to the 1918, 1957 and 1968 pandemics, and is implicated in the current H1N1 2009 outbreak.10 An overv iew of 2009 Pandemic flu H1N1 Under review previous pandemics is detailed in Table 2.11,13

Table 1: Influenza gene segments and functions. Gene segment Protein(s) Function Lineage

NA Neuraminidase Viral progeny release and spread Eurasian swine

M Matrix protein 1 Structural Eurasian swine Matrix protein 2

*HA Haemagglutinin Binds to sialic acid receptors on host cell surface Classical swine

NP Nucleoprotein Encapsidation of viral genome Classical swine

*NS Non-structural protein 1 Inhibits host interferon response; NEP inhibits apoptosis Classical swine

*PB1, PB2, PA Viral polymerase complex Viral RNA replication Swine triple ressortant

*Virulence factors

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Table 3: Diagnostic tests for H1N1 2009. Test Time to complete Sensitivity Specificity PPV NPV

Rapid antigen detection 15 minutes 17.8 93.6 77.4 47.9

Direct fluorescent antibody 2.5 hours 46.7 94.5 91.3 58.9

Viral cell culture 2-3 days 88.9 100 100 87.9

Polymerase chain reaction Up to 6 hours 97.8 100 100 97.3

PPV: positive predictive value; NPV: negative predictive value.

Although the reproduction number of H1N1 2009 is closer to that Treatment strategies of the seasonal flu virus than the devastating 1918 influenza The earlier antiviral therapy is started, the more effective the pandemic, it carries the potential to develop mutations that could treatment is at reducing influenza viral load and the duration of allow more efficient spread between humans, increasing its viral shedding.19,22 Current antiviral treatments include N replication number. inhibitors (oseltamivir and zanamivir) and derivatives ( and rimantidine). Symptoms of pandemic H1N1 Oseltamivir and zanamivir function by blocking progeny virion H1N1 2009 is spread through respiratory droplets, with an release from infected cells, while adamantane and its derivatives incubation time of two to seven days.16 This is considerably longer interfere with intracellular viral uncoating.23 While most strains of than the incubation time of the seasonal influenza A virus, which has pandemic H1N1 have remained susceptible to N inhibitors, been estimated at 1.4 days.17 Models have shown that shedding of adamantane-based drug resistance has been described and these the virus is observed as soon as one day after infection and lasts drugs are not considered to be treatment options for acute seven days,18 allowing for asymptomatic spread. Symptoms of infection.16,24 infection are similar to symptoms of the seasonal influenza virus, Due to its effectiveness against H1N1 2009, many countries have including fever (94%), cough (92%) and sore throat (66%). stockpiled vast quantities of oseltamivir to combat the global Vomiting and diarrhoea are also present in 25% of cases, and pandemic. Unfortunately, resistance to oseltamivir has recently potential faecal–oral spread of the virus must be investigated.1,16 emerged in 31 cases of H1N1 2009 infection.25 Peravimir, an N The majority of previously healthy patients who acquire H1N1 2009 inhibitor that is currently undergoing Phase 3 clinical trials, was will fully recover in one week. authorised for emergency use by the Centers for Disease Control In a study of 272 patients hospitalised with H1N1 2009 infection, (CDC) on October 23, 2009. It has been approved for use in 73% had underlying medical conditions, including , diabetes, severe cases of H1N1 2009, which are not responsive to pregnancy, and neurological disease. Nineteen (7%) died, with a oseltamivir or zanamivir.26 median time from onset of illness to death of 15 days. Zanamivir has shown similar efficacy and safety to oseltamivir with Hospitalisations were seen more frequently in younger patients, with no resistance reported to date, and is effective in treating only 5% of admissions consisting of patients over 65 years old.19 oseltamivir-resistant strains.27,28 Zanamivir is contraindicated in This is in contrast with seasonal influenza, in which the majority of patients with chronic obstructive pulmonary disease (COPD), and hospitalisations occur in the elderly population and children under is delivered using an inhaler, which is difficult to administer two years of age.20 correctly to children and elderly patients.27 Countries are now adding zanamivir to their antiviral stockpiles (which are dominated Diagnosis of pandemic H1N1 by oseltamivir stores); however, a large number of children, COPD Many different variables contribute to making a diagnosis. Clinical patients, and the elderly are currently vulnerable to oseltamivir- suspicion based on current pandemic trends in the community must resistant H1N1 2009.27 be high to cost-effectively carry out diagnostic testing. There are New research has shown that a synergy of oseltamivir, amantadine many techniques readily available to confirm a diagnosis, including and ribavirin (a widely available ) has a two- to 13- rapid antigen testing, direct fluorescent antibody testing, fold increase in antiviral activity against influenza A when polymerase chain reaction (PCR), and cell culture methods. compared to any two of the agents used together in vitro.30 Characteristics of each test are shown in Table 3.21 PCR remains the Additional studies of antiviral treatments for oseltamivir-resistant most robust test for diagnosing pandemic influenza, yielding the H1N1 must be undertaken to ensure the safety and preparedness most sensitive and specific results within a reasonable time period. of the general population in the event of a multidrug-resistant Other tests may be quicker, but are much less sensitive. .

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Vaccination Prevention and infection control Vaccination continues to be the most important primary prevention Prevention of the spread of H1N1 2009 can also be facilitated by measure against influenza spread.31 Both live attenuated and inactivated community interventions. Simple measures such as covering vaccines providing protection from H1N1 2009 have been manufactured coughs and sneezes, washing hands, staying home when sick, for general use, with the first batches administered to the public in early and avoiding close contact with people who are ill can have October 2009. The pandemic H1N1 vaccine is being manufactured in enormous effects on reducing the spread of disease. Households the same way as the annual , using hen’s eggs to grow that initiate the use of facemasks and hand hygiene within the both the pandemic H1N1 virus and an inactive laboratory strain. Hybrid first 36 hours after the onset of flu-like symptoms in a family virions containing surface proteins of the pandemic strain with an member have a reduced incidence of household transmission of inactivated genome are isolated and become the main constituent of the influenza.38 This illustrates the importance of non-medical inactive vaccine.32 A single dose influenza H1N1 vaccine is immunogenic measures for controlling infection and can also be translated to in adults with sufficient protective antibodies produced 14-21 days post the hospital setting, where the use of facemasks, gloves and vaccination.33 Children aged six months to nine years should receive two aprons is recommended when treating infected patients. The use doses of vaccine separated by 21 days to ensure sufficient production of of negative pressure rooms and fit-tested ventilators has been antibodies.34 Side effects are similar to those of the seasonal influenza advised by the CDC, but may not be possible in all centres due vaccine, consisting of injection site tenderness and mild headaches. No to facility and financial limitations.30,39 serious adverse events have been consistently reported. However, there is widespread public concern over the vaccine’s safety,35 which is based on Conclusion fears of rare complications from the vaccine, namely Guillain-Barré Past pandemics have shown that influenza A viruses have great syndrome. Thus far, in the population who have been vaccinated, the potential to cause widespread infections and deaths worldwide. incidence of Guillain-Barré syndrome has not increased over the baseline It is important to stay vigilant in the surveillance and detection rates that are observed in the general population. This is also true for of influenza strains so that future pandemics can be predicted other serious medical conditions.36 Careful vaccine safety surveillance and prevented before they reach advanced stages. While the must be undertaken to detect increases in adverse vaccine reactions over current H1N1 2009 virus has not been as devastating as some background incidences. Since availability of the vaccine will be limited, had forecast, the capability for further, and perhaps more selected countries have initiated prioritisation schedules for vaccine virulent and lethal mutations, still exists.1 Vaccine production recipients in the event of a vaccine shortage. The CDC has advised that must be increased so that new pandemic strains of influenza can populations at risk of serious complications should be vaccinated. This quickly be vaccinated against. A combination of public includes all children and young adults between the ages of six months awareness of the pandemic threat, increased vaccine production and 24 years of age, all people between the ages of 25 and 64 who have technologies, and further development of antiviral treatments is underlying health conditions, healthcare and emergency service workers, the key to being prepared for current and future influenza pregnant women, and people who care for children under the age of six pandemics. months.37

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